The skin is the largest organ system in the body. Clues to the pathogenesis of internal malignancy can be found in dermatological diseases. CS, or multiple hamartoma syndrome, is an autosomal dominant disorder characterized by skin lesions, thyroid lesions, and severe fibrocystic disease of the breast. Most disturbing is descriptive information suggesting that 30-50% of women with CS develop breast cancer. CS, therefore, qualifies as a genetic skin disease which predisposes women to the development of breast cancer. While thought to be a rare disease, the principal investigator has successfully located and examined in detail 15 pedigrees with CS in the New England area. This activity has allowed her to understand better the clinical phenotype of CS, and to gain insight into potential mechanisms that allow for the development of breast cancer in this hereditary disease. Moreover, while preliminary, the principal investigator also hypothesizes that this disease is much more common than originally recognized, and is likely to be one of the more common causes of familial breast cancer. In the studies described in this application, the principal investigator will use three methods to attempt to identify the gene which is mutated in CS. First, the principal investigator will test the hypothesis that the gene that is mutated in Cowden's disease is a specific transcription factor, found on human chromosome 3p, an area thought to contain a tumor suppressor gene important in breast cancer. Second, should the candidate gene strategy prove unsuccessful, the principal investigator has accumulated enough families to perform classic linkage analysis using a panel of polymorphic DNA markers. Finally, the principal investigator will allelotype tumors found in individuals with CS in an effort to use loss of heterozygosity (LOH) to determine sites where a second tumor suppressor allele may be lost and contribute to tumor formation in this disease. In this way, the principal investigator hopes to gain insight into an underrecognized and underdiagnosed form of familial breast cancer which has a cutaneous biomarker of breast cancer susceptibility.